The present invention is novel compounds which are 2-substituted thiazolidinone, oxazolidinone, and imidazolidinone derivatives of fenamic acids and pharmaceutically acceptable acid addition or base salts thereof, pharmaceutical compositions and methods of use thereof. The invention compounds are now found to have activity as inhibitors of one or both of 5-lipoxygenase and cyclooxygenase providing treatment of conditions advantageously affected by such inhibition including inflammation, arthritis, pain, fever and the like. Thus, the present invention is also a pharmaceutical composition or method of use thereof.
Although fenamates are known antiinflammatory agents and various 2-substituted thiazolidinones, oxazolidinones, or imidazolidinones are known as useful substituents in other antiinflammatory agents. For example, together with 3,5 di-tertiary-butyl-4-hydroxy-phenyl groups as disclosed in EP application No. 89 109406.2 and U.S. patent application 499,937 (incorporated herein by reference), the present combination of ring systems, substituents and moieties is not among those previously known.
The following references disclose compounds which contain a single phenyl group, substituted or unsubstituted, attached to a heterocyclic ring structure, through a methylene bridge:
Japanese patent application J6 1012-674-A (Derwent Abstract 86-059691/09) discloses an imidazolidinone compound of the structure ##STR1## with utility as an antiallergic. It lacks the fenamate structure present in the compounds claimed herein.
Denmark patent application DE 3713-094-A (Derwent Abstract 87-307841/44) discloses benzylidene compounds of which compounds of the structure ##STR2## are included, wherein R is 1-18 C straight chain alkyl or 3-18 C branched or cyclic alkyl. These compounds lack the fenamate structure present in the compounds claimed herein. U.S. Pat. No. 4,464,382 discloses compounds of the formula ##STR3## wherein (I) R.sup.1 and R.sup.2 are taken together to represent a tetramethylene or pentamethylene group, (II) R.sup.1 represents a hydrogen atom, and R.sup.2 represents (1) a cycloalkyl or cycloalkenyl group of 4-7 carbon atoms which is unsubstituted or substituted by at least one alkyl group of 1-4 carbon atoms, (2) an anthryl or naphthyl group, (3) a phenyl group which is unsubstituted or substituted, p. 2 (4) a heterocyclic group containing at least one of nitrogen, oxygen, and sulfur atoms which is unsubstituted or substituted (5) a ##STR4## group (wherein R.sup.4 represents a hydrogen atom, a halogen atom, phenyl group, or an alkyl group of 1-5 carbon atoms; and R.sup.5 represents a hydrogen atom, a phenyl group, or an alkyl group of 1-5 carbon atoms) or ##STR5## group; or (III) R.sup.1 and R.sup.2, which may be the same or different with each other, each represents a phenyl group which is unsubstituted or substituted; and R.sup.3 represents a hydrogen atom, an alkyl group of 1-12 carbon atoms, an aralkyl group of 7-13 carbon atoms, a cycloalkyl or cycloalkenyl group of 4-7 carbon atoms which is unsubstituted or substituted by at least one alkyl group of 1-4 carbon atoms, or a phenyl group which is unsubstituted or substituted, possess a strong inhibitory activity on aldose reductase.
Bosin and Campaigne, Intnt'l. J. of Sulfur Chem., Vol. 2 , p. 262 (1972) disclose compounds of the formula ##STR6## wherein X is F or Cl. These compounds also lack the fenamate structure of the present invention.
Four references, U.S. Pat. Nos. 4,173,577; 4,029,815; 4,981,865; and Japanese application publication 24578/67; all disclose fenamate compounds. None of these references, however, discloses oxazolidinone, imidazolidinone, or thiazolidinone derivatives claimed herein.
U.S. Pat. No. 3,719,480 discloses 4-benzylidenerhodanines which differ from the present invention by a para-phenylamino substitution compared to an ortho such substituent. The utility of this patent is as an electrophotographic composition.
Within these disclosures are uses for treating inflammation as are found here, but the differences between known compounds and the present compounds are readily apparent, with no teaching to make obvious that such differences would also be useful for treatment of the conditions taught here.